Despite extensive investigations into the effects of radiation on normal tissues, there is a dearth of agents for mitigating radiation exposure as might occur as a result of terrorist action. We have developed an effective infrastructure for the discovery and development of novel mitigators. The result is a portfolio of about 30 agents that can significantly mitigate acute radiation syndrome (ARS) in murine models, with at least one active against late effect. The next 5 years will be dedicated to prioritizing and optimizing mitigators and identifying targets and biomarkers that will allow their rational use, singly and in combination. Our Cores have met the challenges of our evolving Program with great flexibility. They have taken products through high throughput screening (HTS), chemoinformatics, synthesis, drug optimization, pharmacokinetics, and animal testing, to patenting and licensing. In acknowledgement of their evolving roles, we have renamed them the Product Development Core (PDC) and Product Testing Animal Core (PTAC). They will retain many of their functions in drug discovery, but will reposition themselves towards more advanced product development. The PDC will perform chemical clustering and toxicoinformatics so as to optimize product development. It will integrate its output with our gnotobiotic PTAC that has highly reproducible models of ARS and a large delayed effects (DEARE) program. Drug discovery will be largely a Core activity that is integrated with projects through the actions of an Executive Committee who will prioritize products for development. Projects will study mitigators within contexts of tissue damage that will promote their rational use through target identification. Project 1 will use mitigators to rebalance immune responses that are critical not only for rescue from ARS but also for preventing DEARE. Its interests are closely allied with those of Project 2 that examines a novel subpopulation of myeloid cells that arises after whole body irradiation (WBI). One of our lead mitigators boosts this response and absolutely requires these cells for activity, as may the case for FDA-approved mitigator G- CSF. Their contribution to DEARE and especially cardiomyopathy will also be investigated. Project 3 focuses on restoration of the hematopoietic stem cell niche by factors released by endothelial cells, following their demonstration that pleiotrophin can mitigate hARS. In this renewal they use genetic and pharmacological models to investigate whether protein tyrosine phosphatase receptor sigma modulates the hematopoietic response to WBI. Project 4 builds on the fact that one of our lead compounds mitigates gut radiation damage by looking at its ability to stimulate gut and CNS stem cells through the Wnt pathway. The level of integration between the projects is high as we seek to obtain a deeper understanding of the interactions between tissue damage, innate immune responses, and stem cell recovery processes after WBI and to exploit these to mitigate ARS and DEARE. The Cores are involved in every project and help drive a reiterative, optimized, and prioritized product development process.